Sera and plasma from HIV-1-infected individuals contain antibodies to the virus that cross-react with HLA class I and class II molecules. These observations have been proposed to represent an autoimmune reaction that contributes to disease progression. Regions of homology between viral envelope proteins and class I and class II molecules were identified based on amino acid sequence homology. Viral peptides representing these regions as well as peptides from the gag region of HIV-1 proteins were purchased from a commercial source and tested in an ELISA format with sera from 75 HIV-1-infected individuals. Reactivity to one or more of the peptides was observed in sera from all individuals, particularly with peptides from the gp41 protein. No correlation was found with patterns of reactivity and rates of disease progression. In contrast, HLA class II haplotypes of these individuals were associated with patterns of reactivity of the sera. HLA class II molecules bind peptides that are presented to T-cells initiating and expanding the immune response. Biotinylated peptides were tested for binding to B-cell lines that were homozygous for HLA class II haplotypes. Differential binding patterns were observed with selective peptides by HLA-DRB1 alleles, DQA-DQB alleles, and HLA-DPA2, DPB1 alleles. The most common malignancy in HIV-1-infected individuals is Kaposi's sarcoma (KS). Chang et al. have identified a herpes-like virus sequence in DNA from KS lesions. We identified herpes-like virus sequences in DNA for KS lesions from HIV-1-negative gay men and from individuals with endemic KS from Africa using polymerase chain reaction with primers suggested by Chang et al. Several B-cell lines established from HIV-1-infected individuals were found to contain viral sequences.